Angiotensin II analogues which function as angiotensin II antagonists are useful in the diagnosis and treatment of mammalian hypertension were reported in G. R. Marshal et al., Proc Nat. Acad Sci USA 67, 1624 (1970) and P. A. Khairallah et. al., J. Med Chem. 13, 181 (1970). U.S. Pat. Nos. 3,751,404, 3,886,134, 3,907,762, 3,915,948, 3,923,769, 3,923,770, 3,923,771, 3,925,345, 3,976,770, 4,013,791, 4,179,433, 4,204,991, 4,209,442 and 4,330,532 disclose derivatized peptides incorporating portions of the amino acid sequence of angiotensin II. U.S. Pat. Nos. 4,340,598 and 4,355,040 disclose imidazole derivatives reported to be antagonistic to angiotensin II. The use of angiotensin II antagonists in the treatment of elevated intraocular pressure has not been disclosed.
Glaucoma is an ocular disease complex associated with an elevated pressure within the eye (i.e., intraocular pressure, IOP). As a result of the elevated IOP, damage to the optic nerve resulting in irreversible loss of visual function may ensue. Untreated, this condition may eventually lead to blindness.
Ocular hypertension, i.e., a condition of elevated intraocular pressure without optic nerve damage or characteristic glaucomatous visual field loss, is now believed by the majority of ophthalmologists to represent the earliest phase in the onset of glaucoma.
A number of the drugs presently employed to treat glaucoma are not entirely satisfactory, particularly in the earliest course of the disease when the side effects they produce are often worse than the symptoms of the disease.
Epinephrine, used as a topical solution, must be utilized cautiously in patients with high blood pressure, diabetes, hyperthyroidism and cerebral arteriosclerosis due to the possibility of systemic action.
Timolol, a clinically utilized, topically applied agent for lowering IOP, must be used with caution in patients in whom beta-adrenergic blockade may be undesirable. Systemic absorption of topically administered timolol and the resulting systemic beta-blockade are responsible for the contraindication of timolol therapy in glaucoma patients with compromised pulmonary function and in patients who cannot tolerate its systemic cardiovascular actions.
Pilocarpine, a topical drug, although considered systemically harmless and quite effective, may cause considerable local difficulties. Pupil constriction causes the eye to lose its ability to adapt from light to dark. Accommodation may become so stimulated that the patient's refraction is sometimes incorrect and vision becomes blurred. The drug itself may cause a local vasodilation and red eyes. Irritation is common.
Carbonic anhydrase antagonists have been used systemically but they have a number of disadvantages. While effective in lowering intraocular pressure, they often cause a numbness and tingling, gastrointestinal upsets and, frequently, depression, lethargy, a loss of appetite, and general malaise. European Patent Application 81400326.5, Publication number 36,351, attempts to overcome these difficulties by the topical administration of an alkali metal salt of a carbonic anhydrase antagonist.
The present invention provides a new method for reducing and controlling elevated IOP, especially the elevated IOP associated with glaucoma.